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Viagra Stands Firm Against Muscular Dystrophy

People with muscular dystrophy tire after even light exercise. Now a study suggests that the exhaustion is caused by an enzyme that is missing from the muscle cell membrane, and the results point to a possible treatment for the condition: Viagra.

Every year, about 500 boys in the United States are born with Duchenne muscular dystrophy, the disease's most common form. All forms of muscular dystrophy, which cause skeletal muscles to gradually weaken, result from mutations that overload the body with the enzyme creatine kinase, which breaks down muscle tissue. Researchers have long known that even in milder types of the disease, such as Becker's muscular dystrophy, and in the early stages of Duchenne muscular dystrophy, patients tend to fatigue after relatively minor activities. The briefest walk can leave them far more worn out than would be expected from just having weak muscles.

These effects show up in mouse models of the disease, too. About 3 years ago, Kevin Campbell, a biophysicist at the University of Iowa in Iowa City, showed a video of the tired muscular dystrophy mice in his lab at a conference. A chance comment inspired a possible solution. "One of the physicians in the audience said, 'That looks just like my Becker's [muscular dystrophy] patients,' " Campbell recalls. One of the hallmarks of Becker's muscular dystrophy is the loss of an enzyme, neuronal nitric oxide synthase (nNOS), from muscle cell membranes. Campbell wondered whether the deficiency of nNOS might be the source of fatigue.

nNOS is crucial to provide sufficient blood for contracting muscles, so Campbell and his team examined the blood vessels in mice with muscular dystrophy before and after light exercise. Sure enough, the blood vessels after exercise were narrower than normal, and the capillaries lacked blood--a sign that muscle contraction wasn't working efficiently. Most importantly, the same symptoms showed up in another strain of mice that also lacked nNOS but didn't have muscular dystrophy. And when Campbell biopsied human patients who suffered from various types of muscular dystrophy, he found nNOS was either reduced or absent in almost every one of them. "It wasn't that they were weak," Campbell says. "They were missing nNOS."

Trying to reverse these effects, Campbell treated the mice with the blood-flow-regulating drug sildenafil, better known as Viagra. To Campbell's surprise, it worked. The muscular dystrophy mice and nNOS-deficient mice no longer tired after light exercise. The drug appears to amplify the effects of nNOS elsewhere in the muscle tissue, his team reported online 26 October in Nature, which helps to make up for the enzyme's deficiency in the cell membranes.

"I'm very impressed with this work," says Gregory Cox, a neurobiologist at the Jackson Laboratory in Bar Harbor, Maine. He says he's glad to finally know the role of nNOS in muscle cells and to be able to explain the exaggerated fatigue. He's further encouraged by the fact that an approved drug such as Viagra could help people with muscular dystrophy to be active for longer periods at a time. Not only will that make their lives easier, he says, it could even help slow the disease's progress. As gene therapies that treat muscular dystrophy's underlying cause are still a long way off, any approach that effectively treats a symptom is a big step forward. "It represents a real therapeutic approach that can make a big impact on their quality of life," Cox says.

However, Brian Tseng, a physician and neuroscientist at Massachusetts General Hospital in Boston, cautions against extrapolating the results to humans. He's concerned that if the fatigue were offset and the children exercised more, they might suffer even more rapid muscle degeneration. "We need to be cautious here," he says.